Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV-1 integrase (IN) has emerged as an important therapeutic target for anti-HIV drug development. Its uniqueness to the virus and its critical role in the viral life cycle makes IN suitable for selective inhibition. The recent approval of Raltegravir (MK-0518) has created a surge in interest and great optimism in the field. In our ongoing IN drug design research, we herein report the discovery of substituted analogs of 3-acetyl-4-hydroxy-2-pyranones and their difluoridoborate complexes as novel IN inhibitors. In many of these compounds, complexation with boron difluoride increased the potency and selectivity of IN inhibition. Compound 9 was most active with an IC(50) value of 9 microM and 3 microM for 3'-processing and strand transfer inhibition, respectively.
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PMID:Discovery of 3-acetyl-4-hydroxy-2-pyranone derivatives and their difluoridoborate complexes as a novel class of HIV-1 integrase inhibitors. 1880 96

Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration = 31 nM in 50% human serum). The possible effects of ritonavir and efavirenz on raltegravir pharmacokinetics were separately examined. Two clinical studies of healthy subjects were conducted: for ritonavir plus raltegravir, period 1, 400 mg raltegravir; period 2, 100 mg ritonavir every 12 h for 16 days with 400 mg raltegravir on day 14; for efavirenz plus raltegravir, period 1, 400 mg raltegravir; period 2, 600 mg efavirenz once daily for 14 days with 400 mg raltegravir on day 12. In the presence of ritonavir, raltegravir pharmacokinetics were weakly affected: the plasma concentration at 12 h (C(12 h)) geometric mean ratio (GMR) (90% confidence interval [CI]) was 0.99 (0.70, 1.40), area under the concentration-time curve from zero to infinity (AUC(0-infinity)) was 0.84 (0.70, 1.01), and maximum concentration of drug in serum (C(max)) was 0.76 (0.55, 1.04). In the presence of efavirenz, raltegravir pharmacokinetics were moderately to weakly reduced: C(12 h) GMR (90% CI) was 0.79 (0.49, 1.28); AUC(0-infinity) was 0.64 (0.52, 0.80); and C(max) was 0.64 (0.41, 0.98). There were no substantial differences in the time to maximum concentration of drug in plasma or the half-life. Plasma concentrations of raltegravir were not substantially affected by ritonavir. Though plasma concentrations of raltegravir were moderately to weakly reduced by efavirenz, the degree of this reduction was not clinically meaningful. No dose adjustment is required for raltegravir with coadministration with ritonavir or efavirenz.
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PMID:Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir. 1883 89

For the quantification of the HIV-integrase inhibitor raltegravir in human plasma, dried blood spots and peripheral blood mononuclear cell (PBMC) lysate, an assay was developed and validated, using liquid chromatography coupled with tandem mass spectrometry. The assay also allowed detection, but no quantification due to absence of reference substance, of the main metabolite, raltegravir-glucuronide. Raltegravir was extracted from plasma by means of protein precipitation with a mixture of methanol and acetonitrile using only 50microL plasma. Extraction from dried blood spots was performed with a simple one-step extraction with a mixture of methanol, acetonitrile and 0.2M zincsulphate in water (1:1:2, v/v/v) and extraction from cell lysate was performed in 50% methanol in water. Chromatographic separation was performed on a reversed phase C18 column (150mmx2.0mm, particle size 5microm) with a quick stepwise gradient using an acetate buffer (pH 5) and methanol, at a flow rate of 0.25mL/min. The analytical run time was 10min. The triple quadrupole mass spectrometer was operated in the positive ion-mode and multiple reaction monitoring was used for drug quantification. The method was validated over a range of 50-10,000ng/mL in plasma and dried blood spots and a range of 1-500ng/mL in PBMC lysate. Dibenzepine was used as the internal standard. The method was proven to be specific, accurate, precise and robust. Accuracies ranged from 104% to 105% in plasma, from 93% to 105% in dried blood spots and from 82% to 113% in PBMC lysate. Precision over the complete concentration range was less than 6%, 11% and 13% in plasma, dried blood spots and PBMC lysate, respectively. The method is now applied for therapeutic drug monitoring and pharmacological research in HIV-infected patients treated with raltegravir.
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PMID:Quantification of the HIV-integrase inhibitor raltegravir and detection of its main metabolite in human plasma, dried blood spots and peripheral blood mononuclear cell lysate by means of high-performance liquid chromatography tandem mass spectrometry. 1912 11

Raltegravir, a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has pH-dependent solubility. Raltegravir plasma concentration increases with omeprazole coadministration in healthy subjects; this is likely secondary to an increase in bioavailability attributable to increased gastric pH. Increased gastric pH has been reported in HIV-1-infected individuals, and the effects of omeprazole in this intended population may be diminished. Further investigation is necessary.
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PMID:Effects of omeprazole on plasma levels of raltegravir. 1914 31

The advent of HIV-1 resistance to antiretroviral medications, the need for lifelong antiretroviral therapy (ART) for HIV-infected individuals, and the goal of minimizing ART-related adverse effects and toxicity all drive the need for new antiretroviral drugs. Two new classes of antiretroviral medications for HIV treatment, the CCR5 and integrase inhibitors, have recently been approved for use in patients in whom previous HIV treatment regimens have failed. These new agent classes are a welcome addition to other antiretroviral classes, which include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors. Maraviroc is a CCR5 co-receptor antagonist that blocks HIV binding to the CCR5 receptor, which is a CD4 co-receptor necessary for cell entry. It is approved for use in ART-experienced patients with CCR5-tropic HIV, and was found to significantly reduce HIV viral load and increase CD4+ cell count when combined with an optimized background ART regimen (OBR). Treatment failure with maraviroc has been described and is primarily associated with the presence of CXCR4-tropic virus. Vicriviroc is another CCR5 co-receptor antagonist that is in late clinical trials. Raltegravir is the first US FDA-approved HIV-1 integrase inhibitor. It is approved for use in ART-experienced patients and was found to significantly reduce HIV viral load and increase CD4+ cell counts compared with placebo in combination with an OBR. Raltegravir has also been studied in treatment-naive patients and was found to be non-inferior to an efavirenz-based regimen. Elvitegravir is another HIV-1 integrase inhibitor in clinical development. Other new antiretroviral agents in clinical development include PRO140, a monoclonal antibody against CCR5, and bevirimat, a maturation inhibitor that prevents late-stage gag polyprotein processing. A number of other drug targets, such as CCR5 co-receptor agonists, CXCR4 co-receptor antagonists, novel fusion inhibitors, and alternative antiretroviral strategies, such as immune stimulation and gene therapy, are under investigation.
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PMID:Novel targets for antiretroviral therapy: clinical progress to date. 1919 35

Raltegravir is the first approved human immunodeficiency virus type 1 (HIV-1) integrase inhibitor; it targets the strand transfer step of HIV-1 integration. Clinical trials have demonstrated that raltegravir-containing regimens have potent antiretroviral activity and are well tolerated in HIV-1-infected individuals. In antiretroviral treatment-experienced persons with drug-resistant HIV infection, raltegravir-containing treatment with an optimized background regimen was superior to an optimized background regimen alone. In treatment-naive persons, raltegravir was not inferior to efavirenz when the drugs were administered with tenofovir and lamivudine or emtricitabine. Raltegravir is metabolized by glucuronidation, not hepatically; thus, the potential for drug-drug interactions is decreased. Drug resistance, conferred by substitutions in the gene coding for the HIV-1 integrase enzyme, develops relatively frequently after virologic failure. As an antiretroviral drug with a novel mechanism of action, raltegravir is an important advancement in HIV-1 treatment options.
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PMID:Raltegravir: the first HIV type 1 integrase inhibitor. 1923 80

Raltegravir (RAL) is an HIV integrase inhibitor characterized by potent antiretroviral activity, few adverse effects, and lack of cross-resistance to other antiretroviral (ARV) agents. RAL is emerging as a component of effective alternative ARV therapy for those who experience therapeutic failure or intolerance to reverse transcriptase inhibitors (NRTI and NNRTI) and ritonavir (RTV)-boosted protease inhibitor (PI) containing regimens. The combination of RAL with atazanavir (ATV) without a concomitant NRTI-based backbone or the inclusion of RTV may provide an alternative strategy for those unable to tolerate these latter ARV agents. In this report the authors present a case series of treatment-experienced patients managed with RAL + ATV given without a boosting dose of RTV. All patients tolerated this regimen over a course of 25 to 82 weeks, and had good virologic and immunologic outcome with a decrease in HIV RNA levels to <50 copies/mL and a mean CD4 count increase of 234 cells/mm(3).
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PMID:Raltegravir with unboosted atazanavir 300 mg twice daily in antiretroviral treatment-experienced participants. 1927 Jan 53

Raltegravir (RAL), maraviroc (MVC), darunavir (DRV), and etravirine (ETV) are new antiretroviral agents with significant potential for drug interactions. This work describes a sensitive and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of plasma drug levels. Single-step extraction of RAL, MVC, DRV, ETV and RTV from plasma (100 microl) is performed by protein precipitation using 600 microl of acetonitrile, after the addition of 100 microl darunavir-d(9) (DRV-d(9)) at 1000 ng/ml in MeOH/H(2)O 50/50 as internal standard (I.S.). The mixture is vortexed, sonicated for 10 min, vortex-mixed again and centrifuged. An aliquot of supernatant (150 microl) is diluted 1:1 with a mixture of 20 mM ammonium acetate/MeOH 40/60 and 10 microl is injected onto a 2.1 x 50 mm Waters Atlantis-dC18 3 microm analytical column. Chromatographic separations are performed using a gradient program with 2 mM ammonium acetate containing 0.1% formic acid and acetonitrile with 0.1% formic acid. Analytes quantification is performed by electrospray ionisation-triple quadrupole mass spectrometry using the selected reaction monitoring detection in the positive mode. The method has been validated over the clinically relevant concentrations ranging from 12.5 to 5000 ng/ml, 2.5 to 1000 ng/ml, 25 to 10,000 ng/ml, 10 to 4000 ng/ml, and 5 to 2000 ng/ml for RAL, MRV, DRV, ETV and RTV, respectively. The extraction recovery for all antiretroviral drugs is always above 91%. The method is precise, with mean inter-day CV% within 5.1-9.8%, and accurate (range of inter-day deviation from nominal values -3.3 to +5.1%). In addition our method enables the simultaneous assessment of raltegravir-glucuronide. This is the first analytical method allowing the simultaneous assay of antiretroviral agents targeted to four different steps of HIV replication. The proposed method is suitable for the Therapeutic Drug Monitoring Service of these new regimen combinations administered as salvage therapy to patients having experienced treatment failure, and for whom exposure, tolerance and adherence assessments are critical.
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PMID:A LC-tandem MS assay for the simultaneous measurement of new antiretroviral agents: Raltegravir, maraviroc, darunavir, and etravirine. 1933 96

This study undertook an exploratory data analysis of the binding parameters of HIV-1 integrase inhibitors. The study group involved inhibitors in preclinical development from the diketo acid, pyrroloquinoline and naphthyridine carboxamide families and the most advanced inhibitors Raltegravir and Elvitegravir. Distinct differences were observed in the energetics of binding between the studied classes of inhibitors that also correlated with drug resistant patterns. Quantitative-property-activity-relationships correlated experimental IC(50) values to the binding energy and the logarithm of the partition coefficient between n-octanol and water (clogP). The approach followed here serves as an improved basis for the development of 'second generation' integrase inhibitors.
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PMID:Analysis of binding parameters of HIV-1 integrase inhibitors: correlates of drug inhibition and resistance. 1945 Sep 84

(1) HIV-infected patients who have exhausted most existing antiretroviral treatment options benefit when enfuvirtide or darunavir is added to an optimised multidrug regimen based on the resistance profile; (2) Raltegravir is the first HIV integrase inhibitor to arrive on the market. It was authorised in 2007 in the European Union for patients with multiple antidrug failure; (3) A dose-finding study and two double-blind placebo-controlled trials showed that when raltegravir is added to an optimised antiretroviral regimen about two-thirds of patients achieve undetectable viral load, compared to about one-third of patients treated with an optimised regimen plus placebo. Data are currently limited to 48 weeks. In contrast, adding raltegravir barely increases the efficacy of treatments already containing enfuvirtide and darunavir. Half of patients in whom treatment failed developed viral resistance to raltegravir during these trials; (4) In previously untreated patients, a double-blind controlled trial showed no statistically significant difference in viral load at 48 weeks between raltegravir/tenofovir/lamivudine and efavirenz/tenofovir/lamivudine, but there were only about 40 patients in each group; (5) The adverse effects of raltegravir are poorly documented. In vitro findings, along with the limited clinical data available, point to a potential risk of autoimmune and lymphoproliferative disorders in the long term. (6) Raltegravir is not metabolised by the cytochrome P450 enzyme system, meaning that it should have fewer pharmacokinetic interactions than darunavir. But raltegravir is sensitive to enzyme inducers, which activate its metabolism; (7) Raltegravir is taken orally, twice a day, either during or between meals; (8) In practice, raltegravir is an option for HIV-infected patients with multiple antiretroviral drug failure and few remaining treatment options. It represents an alternative to the darunavir/enfuvirtide combination, and has the advantage of being more convenient to use. Assessment must continue, however, especially in order to identify long-term adverse effects.
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PMID:Raltegravir: new Drug. Alternative to enfuvirtide/darunavir in multidrug-resistant HIV. 1948 91


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